The present invention relates to the field of therapeutics, and more specifically to the use of the klotho protein and related compounds for the treatment and diagnosis of cancer, such as breast cancer and pancreatic cancer as well as other IGF-1 dependent cancers.
Cancer is a group of diseases in which cells grow and divide without respect to normal limits, forming a tumor, and invading and destroying adjacent tissues. Cancer cells may spread to other locations in the body, resulting in a metastatic tumor composed of cells of the same type as those of the original tumor. Cancers are treated in a number of ways including surgery (excision of a tumor), radiation therapy (directed irradiation with X-rays to destroy cancer cells) and chemotherapy (administration of APIs that are more toxic to cancer cells than to non-cancer cells). All these therapies are associated with severe side-effects, and their activity in most types of metastatic cancers is limited.
Common forms of cancer include breast cancer and pancreatic cancer.
Breast cancer, in which malignant cells develop in the tissues of the breast, is the most common cancer among women, and the second most common cause of cancer death in women in the United States. Breast tissue is composed of lobes and ducts and also includes blood vessels and lymph vessels, which are connected to lymph nodes. Clusters of lymph nodes are found near the breast in the axilla, under the arm, above the collarbone, and in the chest. Several different types of breast cancer exist, which vary with respect to the types of cells in which they first appear, the symptoms which develop, and how frequently they occur.
Risk factors for breast cancer include older age, early age onset of menstruation, never having given birth, family history (mother or sister) of breast cancer, radiation therapy to the chest, increased density of breast tissue as identified by mammogram, use of hormones such as estrogen and progesterone, frequent alcohol consumption, race-associated factors, and the presence of particular genetic mutations.
In addition, the presence of benign breast disease is associated with an increased risk of breast cancer. Thus, proliferative lesions without atypia are associated with a 1.5- to 2-fold increased risk of breast cancer, whereas atypical hyperplasias are associated with a 4- to 5-fold increased risk. Currently, there are no markers which can predict increased risk of breast cancer among benign breast disease patients.
Breast cancer can metastasize to almost any other part of the body, including the lymph nodes, bones, liver, lungs, and brain. Metastatic breast cancer is incurable with a median survival period of about 2 years. Breast cancers are treated with surgery, radiation therapy, chemotherapy and, according to specific tumor characteristics, may also also be treated with hormonal therapy or antibodies directed against human epidermal growth factor (HER2) protein. Treatment is also administered before (neo-adjuvant) or after (adjuvant) a surgery in which the primary tumor has been removed, in order to prevent disease recurrence. All forms of therapy, including chemotherapy, radiotherapy hormonotherapy and biological therapy may also be used.
Pancreatic cancer is a malignant tumor of the pancreas. Each year about 33,000 individuals in the United States are diagnosed with this condition, and more than 60,000 in Europe. Depending on the extent of the tumor at the time of diagnosis, the prognosis is generally regarded as poor. Median survival from diagnosis is around 3 to 6 months; 5-year survival is much less than 5%; and complete remission is extremely rare. With 37,170 cases diagnosed in the United States in 2007, and 33,700 deaths, pancreatic cancer has the highest fatality rate of all cancers and is the fourth highest cancer killer in the United States among both men and women. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.
Treatment of pancreatic cancer depends on the stage of the cancer, and includes surgical removal of tumors and chemotherapy. The Whipple procedure is the most common surgical treatment for pancreatic cancers. This procedure is a major surgical operation involving the pancreas, duodenum, and other organs, and carries a significant degree of risk.
Patients diagnosed with pancreatic cancer typically have a poor prognosis partly because the cancer usually causes no symptoms early on, leading to locally advanced or metastatic disease at time of diagnosis. As a result of the aggressive invasion and early metastasis characteristics of the disease, 90% of patients have surgically unresectable disease at the time of diagnosis.
Chemotherapeutic agents for treating cancers in general include alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, hormone receptor modulators, and hormone level modulators. Chemotherapeutic agents are generally associated with severe side effects, due mainly to the inability of the chemotherapeutic agent to distinguish between normal and healthy cells, such that certain fast-growing, normal cells are also attacked. These include blood cells forming in the bone marrow and cells in the digestive tract (mouth, stomach, intestines, esophagus), reproductive system (sexual organs), and hair follicles. Some chemotherapeutic agents may affect cells of vital organs, such as the heart, kidney, bladder, lungs, and nervous system.
Commonly used chemotherapeutic agents for treatment of pancreatic cancer and breast cancer are taxanes, anthracyclines and antimetabolites such as fluorouracil and gemcitabine. Combination therapy with doxorubicin or mitomycin, may also be used. All of these are associated with side effects. For example, fluorouracil commonly causes diarrhea, mouth ulcers, hair thinning or hair loss, and increased risk of infection; and gemcitabine is associated with nausea, swelling of the feet or legs or weight gain due to fluid retention, flu like symptoms such as headache, chills and fever, and increased risk of infection.
The only therapy currently available for metastatic pancreatic cancer is standard chemotherapy (normally using gencitabine, either alone or in combination with capecitabine, erlotinib or platinum agents), which adds about 1 to 2 months to the median survival time.
When the presence of cancer is suspected in a patient, an imaging study is first performed, such as x-ray, ultrasonography or computed tomography. Imaging studies show the presence, location and size of an abnormal mass, but not whether the mass is cancerous. Cancer can only be positively diagnosed by biopsy, which involves removal of a small tissue sample. The biopsy may be performed using fine needle aspiration, wherein a narrow needle is inserted into a lump or tumor, and cells are withdrawn.
Some types of tumors, including breast tumors, may require an excisional biopsy, wherein a whole lump is surgically removed.
Tissue obtained by biopsy is generally analyzed by microscopic analysis of histological sections, which is a time consuming process, requiring a certain amount of subjective evaluation by the pathologist conducting the analysis.
Given the importance of detecting cancer early in its development, and the potential harm that may occur as a result of false positives or false negatives from mammography and other techniques for screening of various types of cancer, a substantial need remains for a more accurate and less invasive means of determining the presence of cancer. Moreover, currently used techniques cannot predict cancer development among patients with benign breast cancer.
It has therefore been desirable to find a treatment for cancer, such as pancreatic cancer and breast cancer, which overcomes at least some of the drawbacks of the background art.
It is further desirable to find a method of diagnosis of cancer which overcomes at least some of the drawbacks of the background art.